1. Field
The invention relates to D-prolines and their use in treating diseases associated with amyloidosis.
2. Description
The compounds (R)-1-[(R)-3-mercapto-2-methyl-propionyl]-pyrrolidine-2-carboxylic acid and (R)-1-[(S)-3-mercapto-2-methyl-propionyl]-pyrrolidine-2-carboxylic acid are disclosed in WO 97/10225 as having antibacterial activity against B. fragilis. These compounds are also disclosed in J. Comput.-Aided Mol. Des., 1(2): 133-42 (1987) in a theoretical study of angiotensin-converting enzyme inhibitors. However, the use of these compounds for treating or preventing central and systemic amyloidosis was not known before the subject invention.
The subject invention provides unique D-proline derivatives that can be used to treat or prevent central and systemic amyloidosis. Amyloidosis is a disorder of protein metabolism in which normally soluble autologous proteins are deposited in tissues as abnormal insoluble fibrils that can cause structural and functional disruption. Disorders associated with amyloidosis include Alzheimer""s disease and maturity onset diabetes mellitus.
The invention relates to D-prolines of the formula: 
wherein
R is SH; benzyl; benzyl substituted by hydroxy or lower alkoxy; phenyl; phenyl substituted by hydroxy or lower alkoxy; or the group 
R1 is hydrogen or halogen;
X is xe2x80x94(CH2)nxe2x80x94; xe2x80x94CH(R2)(CH2)nxe2x80x94; xe2x80x94CH2O(CH2)nxe2x80x94; xe2x80x94CH2NHxe2x80x94; benzyl; xe2x80x94C(R2)xe2x95x90CHxe2x80x94; xe2x80x94CH2CH(OH)xe2x80x94; or thiazol-2,5-diyl;
Y is xe2x80x94Sxe2x80x94Sxe2x80x94; xe2x80x94(CH2)nxe2x80x94; xe2x80x94Oxe2x80x94; xe2x80x94NHxe2x80x94; xe2x80x94N(R2)xe2x80x94; xe2x80x94CHxe2x95x90CHxe2x80x94; xe2x80x94NHC(O)NHxe2x80x94; xe2x80x94N(R2)C(O)N(R2)xe2x80x94; xe2x80x94N[CH2C6H3(OCH3)2]xe2x80x94; xe2x80x94N(CH2C6H5)xe2x80x94; xe2x80x94N(CH2C6H5)C(O)N(CH2C6H5)xe2x80x94; xe2x80x94N(alkoxyalkyl)xe2x80x94; xe2x80x94N(cycloalkyl-methyl)xe2x80x94; 2,6-pyridyl; 2,5-furanyl; 2,5-thienyl; 1,2-cyclohexyl; 1,3-cyclohexyl; 1,4-cyclohexyl; 1,2-naphthyl; 1,4-naphthyl; 1,5-naphthyl; 1,6-naphthyl; biphenyl; 1,2-phenylen; 1,3-phenylen; 1,4-phenylen; 1,2-phenylen substituted by 1 to 4 substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, hydroxy, carboxy, xe2x80x94COO-lower alkyl, nitrilo, 5-tetrazol, (2-carboxylic acid-pyrrolidin-1-yl)-2-oxo-ethoxy, N-hydroxycarbamimidoyl, 5-oxo-[1,2,4]oxadiazolyl, 2-oxo-[1,2,3,5]oxathiadiazolyl, 5-thioxo-[1,2,4]oxadiazolyl, and 5-tert-butylsulfanyl-[1,2,4]oxadiazolyl; 1,3-phenylen substituted by 1 to 4 substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, hydroxy, carboxy, xe2x80x94COO-lower alkyl, nitrilo, 5-tetrazol, (2-carboxylic acid-pyrrolidin-1-yl)-2-oxo-ethoxy, N-hydroxycarbamimidoyl, 5-oxo-[1,2,4]oxadiazolyl, 2-oxo-[1,2,3,5]oxathiadiazolyl, 5-thioxo-[1,2,4]oxadiazolyl, and 5-tert-butylsulfanyl-[1,2,4]oxadiazolyl; and 1,4-phenylen substituted by 1 to 4 substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, hydroxy, carboxy, xe2x80x94COO-lower alkyl, nitrilo, 5-tetrazol, (2-carboxylic acid-pyrrolidin-1-yl)-2-oxo-ethoxy, N-hydroxycarbamimidoyl, 5-oxo-[1,2,4]oxadiazolyl, 2-oxo-[1,2,3,5]oxathiadiazolyl, 5-thioxo-[1,2,4]oxadiazolyl, and 5-tert-butylsulfanyl-[1,2,4]oxadiazolyl;
Xxe2x80x2 is xe2x80x94(CH2)nxe2x80x94; xe2x80x94(CH2)nCH(R2)xe2x80x94; xe2x80x94(CH2)nOCH2xe2x80x94; xe2x80x94NHCH2xe2x80x94; benzyl; xe2x80x94CHxe2x95x90C(R2)xe2x80x94; xe2x80x94CH(OH)CH2; or thiazol-2,5-diyl;
R2 is lower alkyl, lower alkoxy, or benzyl;
 is a single or a double bond; and
n is 0-3,
and to pharmaceutically acceptable salts and mono- and diesters thereof, with the exception of (R)-1-[(R)-3-mercapto-2-methyl-propionyl]pyrrolidine-2-carboxylic acid and (R)-1-[(S)-3-mercapto-2-methyl-propionyl]pyrrolidine-2-carboxylic acid.
A method of using these compounds for treating diseases associated with amyloidosis by administering to a subject in need of such treatment an effective amount of one of the above-identified compounds or (R)-1-[(R)-3-mercapto-2-methyl-propionyl]pyrrolidine-2-carboxylic acid or (R)-1-[(S)-3-mercapto-2-methyl-propionyl]pyrrolidine-2-carboxylic acid is also provided.
The invention will now be described in terms of its preferred embodiments. These embodiments are set forth to aid in understanding the invention but are not to be construed as limiting.
The invention provides compounds of the formulas: 
wherein
R is SH, benzyl or phenyl, optionally substituted by hydroxy or lower alkoxy or the group 
R1 is hydrogen or halogen;
X is xe2x80x94(CH2)nxe2x80x94; xe2x80x94CH(R2)(CH2)nxe2x80x94; xe2x80x94CH2O(CH2)nxe2x80x94; xe2x80x94CH2NHxe2x80x94; benzyl, xe2x80x94C(R2)xe2x95x90CHxe2x80x94; xe2x80x94CH2CH(OH)xe2x80x94; or thiazol-2,5-diyl;
Y is xe2x80x94Sxe2x80x94Sxe2x80x94; xe2x80x94(CH2)nxe2x80x94; xe2x80x94Oxe2x80x94; xe2x80x94NHxe2x80x94; xe2x80x94N(R2)xe2x80x94; xe2x80x94CHxe2x95x90CHxe2x80x94; xe2x80x94NHC(O)NHxe2x80x94; xe2x80x94N(R2)C(O)N(R2)xe2x80x94; xe2x80x94N[CH2C6H3(OCH3)2]xe2x80x94; xe2x80x94N(CH2C6H5)xe2x80x94; xe2x80x94N(CH2C6H5)C(O)N(CH2C6H5)xe2x80x94; xe2x80x94N(alkoxyalkyl)xe2x80x94; xe2x80x94N(cycloalkyl-methyl)xe2x80x94; 2,6-pyridyl; 2,5-furanyl; 2,5-thienyl; 1,2-cyclohexyl; 1,3-cyclohexyl; 1,4-cyclohexyl; 1,2-naphthyl; 1,4-naphthyl; 1,5-naphthyl; 1,6-naphthyl; biphenyl; or 1,2-phenylen, 1,3-phenylen and 1,4-phenylen, wherein the phenylen groups are optionally substituted by 1-4 substituents, selected from halogen, lower alkyl, lower alkoxy, hydroxy, carboxy, xe2x80x94COO-lower alkyl, nitrilo, 5-tetrazol, (2-carboxylic acid-pyrrolidin-1-yl)-2-oxo-ethoxy, N-hydroxycarbamimidoyl, 5-oxo-[1,2,4]oxadiazolyl, 2-oxo-[1,2,3,5]oxathiadiazolyl, 5-thioxo-[1,2,4]oxadiazolyl and 5-tert-butylsulfanyl-[1,2,4]oxadiazolyl;
Xxe2x80x2 is xe2x80x94(CH2)nxe2x80x94; xe2x80x94(CH2)nCH(R2)xe2x80x94; xe2x80x94(CH2)nOCH2xe2x80x94; xe2x80x94NHCH2xe2x80x94; benzyl, xe2x80x94CHxe2x95x90C(R2)xe2x80x94; xe2x80x94CH(OH)CH2; or thiazol-2,5-diyl;
R2 is lower alkyl, lower alkoxy or benzyl and
n is 0-3,
and pharmaceutically acceptable salts or mono- and diesters thereof, with the exception of (R)-1-[(R)xe2x80x94 and (R)-1-[(S)-3-mercapto-2-methyl-propionyl]-pyrrolidine-2-carboxylic acid.
The compounds of formulas I-A or I-B may contain 4 or 2 asymmetric carbon atoms. Accordingly, the present invention includes all sterioisomeric forms of the compounds of formula I-A or I-B, including each of the individual enantiomers and mixtures thereof.
It has been surprisingly found that the D-prolines of formula I-A and I-B can be used in the treatment or prevention of all forms of central and systemic amyloidosis, which is a disorder of protein metabolism in which normally soluble autologous proteins are deposited in the tissues as abnormal insoluble fibrils, which cause structural and functional disruption. The most common disorders associated with amyloidosis are Alzheimer""s disease (AD), maturity onset diabetes mellitus, or amyloidosis
as a significant cause of non-ischaemic heart failure,
as complication of long term haemodialysis in renal failure,
as complication of monoclonal gammopathies,
from chronic inflammatory disorders,
from chronic infections or
from certain types of cancer.
Furthermore, amyloidosis comprises many different diseases such as forms of hereditary amyloidosis most common familial amyloid polyneuropathy (FAP), scrapie and Kreuzfeld-Jakob disease.
The common pathological feature is extracellular deposition of so called amyloid proteins in B-structured fibers and the same staining characteristics.
Serum amyloid P component (SAP) is a normal plasma protein and the precursor of amyloid component, a universal constituent of the abnormal tissue deposits in amyloidosis. It is resistant to proteases and therefore plays a key role in the persistance of amyloid in vivo. For therapy pharmaceutically active compounds have to be found which would prevent the interaction of SAP with amyloid fibrils. This interaction has been demonstrated to be a protein fiber interaction, rather than an interaction with more general fiber components such as glycosaminoglycans. SAP consists as a pentamer of 5 identical non-covalently associated subunits. Two pentamers can non-covalently associate to a decamer with the two pentameric disk-like rings interacting face to face. SAP is a calcium-dependent ligand binding protein. It is produced and degraded exclusively in hepatocytes and extremely stabile outside the liver.
The participation of SAP in the pathogenesis of amyloidosis in vivo confirms that inhibition of binding to amyloid fibrils is an attractive therapeutic target in a range of serious human diseases.
Objects of the present invention are the aforementioned compounds of formula I-A and I-B and salts and esters thereof per se and as therapeutically active substances, their manufacture and their use for therapeutic purposes and, respectively, for the production of corresponding medicaments as well as medicaments containing a compound of formula I-A and I-B or a salt thereof and the production of such medicaments for said purpose.
The term xe2x80x9clower alkylxe2x80x9d denotes straight-chain or branched-chain saturated hydrocarbon residues, preferably with 1-4 C atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, 2-butyl, isobutyl and t-butyl.
xe2x80x9cHalogenxe2x80x9d denotes chlorine, iodine, fluorine and bromine.
Compounds of formula I-A and I-B can form salts with metals, e.g. alkali metal salts such as sodium or potassium salts or alkaline earth metal salts such as calcium or magnesium salts, with organic bases, e.g. salts with amines such as N-ethylpiperidine, procaine or dibenzylamine, or salts with basic amino acids such as salts with arginine or lysine. These salts can be formed and isolated by methods well known in the art.
The compounds can also be used in the ester form, such esters being aliphatic or aromatic, such as, for example alkyl and phenolic esters. The most preferred esters are alkyl esters derived from C1-4 alkanols, especially methyl and ethyl esters. The compounds of formulas I-A and I-B can also be used in form of their prodrugs at either one or both carbonyl functions. Examples are esters, intramolecular esters, phosphate esters, double esters, glycolamide esters, glyceride conjugates, dihydropyridine derivatives or 8-(hydroxymethyl)-1-naphthylmethyldisulfide esters. The prodrugs may add to the value of the present compounds advantages in absorption, pharmacokinetics in distribution and transport to the brain. (WO 9514705; H. Bundgaard et al., Drugs of the Future, 16: 443 (1991); A. N. Saab et al., Pharmaceutical Science, 79:802 (1990); D. M. Lambert et al., Current Medical Chemistry, 1:376 (1995).
Preferred are compounds of formula I-A. Especially preferred compounds of formula I-A in the scope of the present invention are those in which X is CH(R2)(CH2)nxe2x80x94 and wherein R2 is methyl or methoxy and, n is 0 or 1.
The following are examples of such compounds:
(R)-1-[(S)-3-[(S)-3-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-methyl-3-oxopropyldisulfanyl]-2-methyl-propionyl]-pyrrolidine-2-carboxylic acid,
(R)-1-[8-[(R)-2-Carboxy-pyrrolidin-1-yl)-2,7-dimethyl-8-oxo-octanoyl]-pyrrolidine-2-carboxylic acid,
(R)-1-[8-[(R)-2-Carboxy-pyrrolidin-1-yl]-2,7-dimethoxy-8-oxo-octanoyl]-pyrrolidine-2-carboxylic acid and
(R)-1-[6-[(R)-2-Carboxy-pyrrolidin-1-yl)-2,5-dimethyl-6-oxo-hexanoyl]-pyrrolidine-2-carboxylic acid (mixture of 3 diastereomers)
Especially preferred are also compounds, in which X is xe2x80x94(CH2)nxe2x80x94 and n is 0 or 1.
Such compounds are:
(R)-1-[7-[(R)-2-Carboxy-pyrrolidin-1-yl]-7-oxo-heptanoyl]-pyrrolidine-2-carboxylic acid,
(R)-1-[6-[(R)-2-Carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylic acid,
(R)-1-[5-[(R)-2-Carboxy-pyrrolidin-1-yl]-5-oxo-pentanoyl]-pyrrolidine-2-carboxylic acid,
(R)-1-[[4-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethyl]-phenyl]acetyl]-pyrrolidine-2-carboxylic acid,
(R)-1-[[3-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-ureido]-pyrrolidine-2-carboxylic acid,
(R)-1-[[Benzyl-[2-[(R)-2-carboxy-pyrrolidin-1-yl]-2-oxo-ethyl]-amino]-acetyl]-pyrrolidine-2-carboxylic acid,
(R)-1-[cis-4-[(R)-2-Carboxy-pyrrolidine-1-carbonyl]-cyclohexanecarbonyl]-pyrrolidine-2-carboxylic acid and
(R)-1-[[3-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethyl]-phenyl]-acetyl]-pyrrolidine-2-carboxylic acid.
Preferred are further compounds of formula I-A, wherein X is xe2x80x94CH2Oxe2x80x94.
Examples of such compounds are the following:
(R)-1-[[2-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]-acetyl]-pyrrolidine-2-carboxylic acid,
(R)-1-[[4-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]-acetyl]-pyrrolidine-2-carboxylic acid,
(R)-1-[[4-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-2-methoxy-phenoxy]-acetyl]-pyrrolidine-2-carboxylic acid,
(R)-1-[[3-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]-acetyl]-pyrrolidine-2-carboxylic acid,
(R)-1-[[3-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-2-methyl-phenoxy]-acetyl]-pyrrolidine-2-carboxylic acid and
(R)-1-[[5-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-naphthalen-1-yloxy]-acetyl]-pyrrolidine-2-carboxylic acid.
Compounds in which X is xe2x80x94CH2NH are further preferred.
An example of such a compound is
(R)-1-[[4-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethylamino]-phenylamino]-acetyl]-pyrrolidine-2-carboxylic acid.
Compounds, in which X is xe2x80x94CH2CH(OH)xe2x80x94 are further preferred.
Such a compound is, for example,
(2E,4E)-(R)-1-[6-[(R)-2-Carboxy-pyrrolidin-1-yl]-2,5-dimethyl-6-oxo-hexa-2,4-dienoyl]-pyrrolidine-2-carboxylic acid.
The aforementioned compounds of formula I-A and I-B can be manufactured in accordance with the invention by
a) converting a compound of formula 
xe2x80x83into a compound of formula 
xe2x80x83and then into a compound of formula 
xe2x80x83wherein R1, X and Xxe2x80x2 have the significances given above and R2 is lower alkyl, or
b) treating a compound of formula 
xe2x80x83with a compound of formula 
xe2x80x83to a compound of formula I-A by cleaving off the protecting group,
wherein X, Y and Xxe2x80x2 have the significances given above and R4 is hydroxy or halogen, or
c) reacting a compound of formula 
xe2x80x83with an amine of formula
NH2R5 
and cleaving off the protecting group from a compound of formula 
xe2x80x83wherein R1 and R3 are described as above and R5 is hydrogen, lower alkyl, lower alkoxy, benzyl, lower alkoxyalkyl, cycloalkyl-methyl or
xe2x80x94CH2C6H3(OCH3)2, or
d) reacting a compound of formula 
xe2x80x83with a compound of formula 
xe2x80x83and cleaving off the protecting group of a compound of formula 
xe2x80x83wherein R1, R3 and X have the significances given above, or
e) reacting a compound of formula 
xe2x80x83with a compound of formula 
xe2x80x83and cleaving off the protecting group of compounds of formula 
xe2x80x83wherein R1, R3 and X have the significances given above and R7 is halogen, lower alkyl, lower alkoxy, hydroxy, carboxy, xe2x80x94COO-lower alkyl, nitrilo, 5-tetrazol, (2-carboxylic acid-pyrrolidin-1-yl)-2-oxo-ethoxy, N-hydroxycarbamimidoyl, 5-oxo-[1,2,4]oxadiazolyl, 2-oxo-[1,2,3,5]oxathiadiazolyl, 5-thioxo-[1,2,4]oxadiazolyl and 5-tert-butylsulfanyl-[1,2,4]oxadiazolyl, and m is 0-4, or
f) cleaving off a protecting group from a compound of formulas 
xe2x80x83wherein R, R1, X, Y and Xxe2x80x2 is as described as above and R3 is a protecting group, to give a compound of formula I-A or I-B, and, if desired,
converting a compound of formulas I-A and I-B into a pharmaceutically usable salt or into a mono- and diester.
In accordance with process variant (a) a compound of formula I-A-1 is obtained by converting a compound of formula II, for example 1-[(S)-3-acetylsulfanyl-2-methyl-propionyl]-(R)-pyrrolidine-2-carboxylic acid, into a compound of formula I-B-1 and then into a compound of formula I-A-1. The reaction is conveniently effected under inert atmosphere at room temperature in the presence of ammonia in a solvent, such as methanol. After stirring for about 2 hours the compound is separated and subsequently the reaction product can be worked-up to the desired pure product according to generally known methods.
The compounds of formula I-A-1 are obtained by stirring the above compound in a solution of CuSO4 in water at room temperature.
The precise reaction conditions are described in more detail in the working Examples.
In accordance with reaction step (b) a protected D-proline is treated with a corresponding dicarboxylic acid or with a corresponding acetyl halide at 0xc2x0 C. The following dicarboxylic acids are preferred: 2,4-dimethylglutaric acid, 2,3-dimethylsuccimic acid, cyclohexane-1,4-dicarboxylic acid, cyclohexane-1,3-dicarboxylic acid, cyclohexane-1,2-dicarboxylic acid, 1,4-phenylenediacetic acid, 1,3-phenylenediacetic acid, benzene-1,4-dioic acid, benzene-1,3-dioic acid, pyridine-2,6-dicarboxylic acid, thiophene-2,5-dicarboxylic acid, furan-2,5-dicarboxylic acid, adipic acid, 1,4-phenylenediacetic acid, 1,2-phenylenediacetic acid, (4-carboxymethyl-naphthylen-1-yl)acetic acid, (6-carboxymethyl-pyridin-2-yl)acetic acid, (5-carboxymethyl-thiophen-2-yl acetic acid, 2,5-dimethoxy-hexanedioic acid, 2,5-dibenzyl-hex-3-enedioic acid or 2,5-diisopropyl-hex-3-enedioxic acid. A detailed procedure is descriped in the Examples in the General Procedure A.
The reaction step (c) describes the treatment of an amine, for example propylamine, cyclopropylmethylamine, methoxyethylamine, benzylamine or veratrylamine with a compound of formula IX. This reaction is carried out at a temperature between 20 and 80xc2x0 C. in a solvent, such as acetonitrile.
In accordance with variant (d) a compound of formula I-B is prepared. To a compound of formula XV in dichloromethane at 0xc2x0 C. is added a corresponding bromacetyl derivative, such as bromacetyl bromide, and a compound of formula V. The deprotection is than carried out by methods known in the art.
Compounds, in which Y is an optionally substituted 1,2-, 1,3- or 1,4-phenylen group, can be prepared in accordance with reaction variant (e). To a compound of formula XV a corresponding dihydroxy-derivative of formula XVII is added. The reaction is carried out in dimethylformamide at room temperature. Preferred are the following dihydroxy-derivatives: hydroquinone, tetrafluorohydroquinone, chorohydroquinone, methoxyhydroquinone, resorcinol, 2,6-dihydroxytoluene, 5-methoxyresorcinol, 3,5-dihydroxybenzoate, 3,5-dihydroxybenzonitrile, phloroglucinol, pyrogallol-1-methyl ether, 3-methylcatechol, tetrachlorocatechol, 2,6-dihydroxynaphthalene, 1,5-dihydroxynaphthalene, 2,3-dihydroxynaphthalene, 2,2xe2x80x2-dihydroxybiphenyl, 1,4-naphthoquinone or 2,7-dihydroxynaphthalene.
In accordance with process variant (f), a compound of formulas III or IV is deprotected to a compound of formula I-A or I-B. Suitable protecting groups and methods for their cleavage will be familiar to any person skilled in the art, although of course there can be used only those protecting groups which can be cleaved off by methods under the conditions of which other structural elements are not affected. The tert-butyl group and the benzyl group are preferred O-protecting groups. The process is carried out in conventional manner. For example, a compound of formula III can be dissolved in a suitable solvent or mixture of solvents such as ethanol and ethylacetate, and hydrogenated in the presence of Pd on carbon at room temperature and atmospheric pressure.
Pharmaceutically acceptable salts and esters can be manufactured according to methods which are known per se and familiar to any person skilled in the art.
In schemes 1-9 are described processes for preparation of compounds of formulas I-A and I-B, starting from known compounds or from compounds, which can be prepared in conventional manner.
The starting materials of formulas V, VI, VII, IX, X, XII, XIV, XVII, XX and XXIV are commercial products or can be prepared according to methods known per se.
The preparation of compounds of formulas I-A and I-B are described in more detail in working Examples 1-104. 
wherein R1, X and Xxe2x80x2 have the significances given above, R2 is lower alkyl and R3 is a protecting group. 
wherein X, Y and Xxe2x80x2 have the significances given above and R4 is hydroxy or halogen. 
wherein R1 and R3 are described as above and R4 is hydrogen, lower alkyl, lower alkoxy, benzyl, lower alkoxyalkyl, cycloalkyl-methyl or xe2x80x94CH2C6H3(OCH3)2. 
wherein R1, R3, X and Xxe2x80x2 have the significances given above and R6 is hydrogen, lower alkyl, lower alkoxy, or benzyl. 
w wherein R1, R3 and X have the significances given above. 
wherein R1, R3 and X have the significances given above and R7 is halogen, lower alkyl, lower alkoxy, hydroxy, carboxy, xe2x80x94COO-lower alkyl, nitrilo, 5-tetrazol, (2-carboxylic acid-pyrrolidin-1-yl)-2-oxo-ethoxy, N-hydroxycarbamimidoyl, 5-oxo-[1,2,4]oxadiazolyl, 2-oxo-[1,2,3,5]oxathiadiazolyl, 5-thioxo-[1,2,4]oxadiazolyl and 5-tert-butylsulfanyl-[1,2,4]oxadiazolyl, and m is 0-4. 
wherein R1, R3, R5, X and Xxe2x80x2 have the significances given above. 
wherein R1 and R2 have the significances given above. 
wherein R3 has the significance given above.
The preparation of the following examples is described in more detail:
As mentioned earlier, the compounds of formulas I-A and I-B have valuable pharmacological properties. They can be used against all forms of central and systemic amyloidosis, which is a disorder of protein metabolism in which normally soluble autologous proteins are deposited in the tissues as abnormal insoluble fibrils, which cause structure and functional disruption.
Compounds of formula I-A and I-B have been tested by the following method:
Test method
Binding of SAP (serum amyloid P) to human amyloid Axcex2(1-42) fibrils
Nunc Flouro Polysorp 96 well plates were coated with 0.5 xcexcg/well of Axcex21-42, which had been aged for 7 days at 37xc2x0 C. Plates were dried for 3 days at 37xc2x0 C., washed with 2xc3x97150 xcexcl of TC (10 mM tris, 138 mM NaCl, 6 mM CaCl2, 0.05% NaN3 pH 8.0) with 1% bovine serum albumin. Then 50 xcexcl TC containing 8% bovine serum albumin, 25 xcexcl compound in TC and 25 xcexcl 40 nM [125I]serum amyloid protein in TE (10 mM EGTA instead of Ca) were added per well. Incubation was performed over night at room temperature and wells were washed twice with 180 xcexcl of TC containing 1% bovine serum albumin. To determine radioactivity 100 xcexcl Microscint 40 were added per well and radioactivity was measured in a TopCount (Packard).
The IC50 (xcexcM) of preferred compounds of formula I-A and I-B are in the range of about 0.2-2.0.
The compounds of formulas I-A and I-B and their pharmaceutically acceptable acid addition salts, their mono- and diesters and cyclic imides thereof can be used as medicaments (e.g. in the form of pharmaceutical preparations). Pharmaceutical preparations can be administered orally (e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions). Administration can, however, also be effected rectally (e.g. in the form of suppositories), parenterally (e.g. in the form of injection solutions), or nasally.
For the manufacture of pharmaceutical preparations, the compounds of formulas I-A and I-B and the pharmaceutically acceptable acid addition salts and esters thereof can be processed with pharmaceutically inert, inorganic or organic carriers. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oil, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the manufacture of solutions and syrups are, for example, water, polyols, glycerol, vegetable oils and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
The pharmaceutical preparations can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, coating agents or antioxidants. They can also contain other therapeutically valuable substances.
Medicaments containing a compound of formulas I-A or I-B or a pharmaceutically acceptable acid addition salt or mono- and diesters thereof and a therapeutically inert barrier are also an object of the present invention, as is a process for their manufacture which comprises bringing one or more compounds of formulas I-A and I-B and/or pharmaceutically acceptable acid addition salts and mono- and diesters thereof into a galenical administration form together with one or more therapeutically inert carriers.
In accordance with the invention, compounds of formulas I-A and I-B as well as their pharmaceutically acceptable acid addition salts and mono- and diesters thereof can be used used in the treatment or prevention of central and systemic amyloidosis.
The most common disorders associated with amyloidosis are Alzheimer""s disease (AD), maturity onset diabetes mellitus, or amyloidosis
as a significant cause of non-ischaemic heart failure,
as complication of long term haemodialysis in renal failure,
as complication of monoclonal gammopathies,
from chronic inflammatory disorders,
from chronic infections and
from certain types of cancer.
Furthermore, amyloidosis comprises many different diseases such as forms of hereditary amyloidosis, most commonly familial amyloid polyneuropathy (FAP), scrapie and Kreuzfeld-Jakob disease.
Furthermore, the present compounds can be used for the manufacture of corresponding medicaments. The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In the case of oral administration the dosage lies in a range of about 0.1 mg per dosage to about 5,000 mg per day of a compound of formulas I-A or I-B or the corresponding amount of a pharmaceutically acceptable acid addition salt or mono- and diesters thereof. The upper limit can, of course, be exceeded when indicated to be appropriate.
The following Examples illustrate the present invention in more detail. However, they are not intended to limit its scope in any manner. All temperatures are given in degrees Celsius.